The present invention is directed to novel synthetic methods in the manufacture of pharmaceutically active pyrazolopyrolidines, and pyrazolopyrolidine intermediates in the manufacture of pharmaceutically active compounds. The present invention is further directed to intermediates useful in the disclosed process.
The synthesis of pyrazolopyrolidines has previously been described in PCT international patent application WO 2010/056708. The syntheses taught in Intermediate 6 of WO 2010/056708 yielded a 1:1 mixture of products of formulas Ia and Ib:
WO 2010/056708 taught an additional step of resolution of the desired product Ib by column chromatography.
The pyrazolopyrolidines of structural formula Ib described in WO 2010/056708 are used in processes to synthesize effective DPP-IV inhibitors, such as formula IIb:

A regioisomer-selective process, yielding a greater percentage of the desired pyrazolopyrolidine regioisomer product, was desired. The inventors have now discovered efficient regioisomer-selective processes, comprising sulfonylation of the pyrazolopyrolidines and isomerization of the sulfonylated pyrazolopyrolidines.